THE INVOLVEMENT OF POTASSIUM CHANNELS IN THE ACTION OF CICLAZINDOL IN RAT PORTAL-VEIN

1 In whole portal veins, ciclazindol (0.3-10-mu-M) increased the amplitude and duration, but decreased the frequency of spontaneous contractions. Glibenclamide (0.3-10-mu-M) produced a small increase in contraction amplitude and duration with a small reduction in contraction frequency. 2 In whole portal veins, ciclazindol (1-10-mu-M) antagonized the relaxant effects of BRL 38227 in a non-competitive manner. Under identical conditions, the effects of glibenclamide (0.3-10-mu-M) appeared to be competitive. 3 In whole portal veins loaded with K-42, ciclazindol itself (up to 3-mu-M) had no detectable effect on basal K-42 exchange. However, the increase in K-42 efflux produced by BRL 38227 (5-mu-M) was antagonized by ciclazindol (3-mu-M). Similar effects were produced by glibenclamide (up to 3-mu-M). 4 In freshly-isolated portal vein cells examined by the whole-cell voltage-clamp technique, ciclazindol (1-100-mu-M) inhibited the slowly-activating and inactivating transient outward current (I(TO)) which could be generated at potentials more positive than -30 mV. In addition ciclazindol (1-10-mu-M) inhibited the non-inactivating K-current (I(KCO)) induced by BRL 38227 (10-mu-M). 5 In freshly-isolated portal vein cells under current-clamp conditions, the hyperpolarization produced by BRL 38227 (10-mu-M) was reversed by ciclazindol (1-10-mu-M). 6 In porcine brain membrane fragments, glibenclamide (0.65 nm) displaced 50% of the binding of [H-3]-glibenclamide whereas ciclazindol (up to 10-mu-M) had no effect. 7 It is concluded that ciclazindol is a K-channel blocker. Its action is not selective for the channel(s) which carry I(KCO) but also extends to those which carry I(TO). Its inability to displace [H-3]-glibenclamide from porcine brain fragments may indicate that antagonism of BRL 38227 by ciclazindol in smooth muscle is exerted at a site different from that of glibenclamide.